Structural and functional insights into the role of the N-terminal Mps1 TPR domain in the SAC (spindle assembly checkpoint)
Structural and functional insights into the role of the N-terminal Mps1 TPR domain in the SAC (spindle assembly checkpoint)
复制标题
对 N 端 Mps1 TPR 结构域在 SAC（纺锤体组装检查点）中的作用的结构和功能见解。
DOI：
10.1042/bj20121448
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发表时间：
2012-12-15
影响因子：
4.1
通讯作者：
Bolanos-Garcia, Victor M.
中科院分区：
文献类型：
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作者：
Thebault, Philippe;Chirgadze, Dimitri Y.;Bolanos-Garcia, Victor M.
纺锤体组装检查点（SAC）是一种监测系统，确保遗传物质及时准确地传递给后代。这一过程暗示着着丝点靶向有丝分裂激酶Bub1（不受苯甲胺1的出芽抑制）、BubR1（与Bub1相关）和Mps1（单极纺锤体1），这是由每个激酶的n端介导的。在本研究中，我们报道了1.8 Å （1 Å=0.1 nm）的TPR（四肽重复）结构域在人类Mps1的n端区域的晶体结构。该结构揭示了与有丝分裂检查点激酶Bub1和BubR1的TPR基元的总体高度相似性，以及许多独特的特征，包括无着丝点结构成分KNL1的结合位点（着丝点-null 1； blinkin）和二聚化的决定因素。此外，我们发现在Mps1的最n端有一段氨基酸是二聚体形成所必需的，干扰二聚体的形成会导致激酶活性的错误定位和错误调节。本研究的结果为Mps1有丝分裂功能的分子细节提供了重要的见解，包括决定底物选择性和着丝点对接的特征。
The SAC (spindle assembly checkpoint) is a surveillance system that ensures the timely and accurate transmission of the genetic material to offspring. The process implies kinetochore targeting of the mitotic kinases Bub1 (budding uninhibited by benzamidine 1), BubR1 (Bub1 related) and Mps1 (monopolar spindle 1), which is mediated by the N-terminus of each kinase. In the present study we report the 1.8 Å (1 Å=0.1 nm) crystal structure of the TPR (tetratricopeptide repeat) domain in the N-terminal region of human Mps1. The structure reveals an overall high similarity to the TPR motif of the mitotic checkpoint kinases Bub1 and BubR1, and a number of unique features that include the absence of the binding site for the kinetochore structural component KNL1 (kinetochore-null 1; blinkin), and determinants of dimerization. Moreover, we show that a stretch of amino acids at the very N-terminus of Mps1 is required for dimer formation, and that interfering with dimerization results in mislocalization and misregulation of kinase activity. The results of the present study provide an important insight into the molecular details of the mitotic functions of Mps1 including features that dictate substrate selectivity and kinetochore docking.